Identifying the mechanisms underlying opioid-mediated effects on the immune system is extremely relevant not only to our understanding of the impact of drugs of abuse during the course of HIV infection but also for the clinical use of narcotics for pain management. Our studies have demonstrated the acute activation of central opioid receptors results in a profound suppression of blood lymphocyte responses and following chronic morphine administration, these cells have a heightened sensitivity to the compensatory neuroadaptive changes that accompany drug withdrawal or exposure to stress. Using oligonucelotide array technology, we have discovered that acute morphine administration results in significant alterations in gene expression of blood leukocytes that suggest functional deficits in both antigen presenting cells and lymphocytes. Several genes involved in the synthesis and intracellular processing of MHC II were found to be down-regulated whereas selected genes which suppress proliferation and cytokine production were up-regulated To filrther investigate the relevance of these findings, in the first specific aim of the proposed studies we will determine the temporal and dose dependency of the effects of acute morphine on gene expression in blood leukocytes. In the second specific aim, experiments will address the opioid-receptor specificity and peripheral in vivo pathways involved in producing the effects of morphine on leukocyte gene expression. In the third specific aim, gene expression will be determined in animals that have undergone compensatory neuroadapfive mechanisms following chronic morphine treatment and during sudden withdrawal states. Each specific aim will be carried out in a three-tiered fashion which will include 1) a global assessment ofgene expression using oligonucelotide array analysis, 2) FACs analysis to identify changes in leukocyte phenotypes and protein content in specific cell types and 3) MHC dependent and independent functional immune cell assays. Through the use of this well-def'med animal model,we are now in a position to evaulate both the neurological and immunological targets which may contribute to the increased rate of HIV replication and susceptibility to infectious diseases that accompanies drug abuse.